Background: Apatinib is an orally administered, highly selective tyrosine kinase inhibitor of VEGFR-2 that has been studied in many clinical trials, primarily in China, treating various solid tumors. Based on the results of the Chinese Phase 3 study, apatinib was approved in China for the treatment of advanced gastric cancer (GC), but apatinib has yet to be evaluated in a randomized placebo-controlled study in the rest of the world. ANGEL is a multinational, placebo controlled, Phase 3 study investigating the efficacy and safety of apatinib in advanced GC patients in North America, Europe, and Asia Pacific. Methods: Main eligibility criteria include patients with advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction for whom at least 2 prior lines of standard chemotherapy had failed, ECOG performance status ≤ 1, and disease progression < 6 months after last chemotherapy treatment. Approximately 459 patients will be randomized in a 2:1 ratio to receive continuous 28-day cycles of apatinib 700 mg or a matched placebo daily with best supportive care until disease progression, intolerable toxicity or withdrawal of consent. Stratification factors include geographic region (Asia vs. North America/Europe), disease measurability, prior ramucirumab treatment, and treatment therapy line (3^rd or 4^th). Primary endpoint is overall survival (OS) in the intent-to-treat population, and secondary endpoints are progression free survival (PFS), objective response rate (ORR), disease control rate (DCR), quality of life, and safety. The primary analysis of OS will be conducted in intention-to-treat population using a stratified log-rank test at the two-sided alpha = 0.05 level of significance. If the primary analysis of OS is statistically significant, then PFS and ORR will be analyzed. All other secondary efficacy endpoints will be analyzed using two-sided tests at the alpha = 0.05 level of significance. Enrollment opened Feb 2017. Clinical trial information: NCT03042611